Inflammation and iron deficiency are two major causes of anaemia in disease-endemic setting. A deficiency in iron supply leads to an imbalance in the homeostatic environment of the body spurring a series of acute phase responses and leading to inflammation. Inflammation leads to more iron retention [17], and then iron deficiency which further causes inflammation and subsequent anaemia. This vicious cycle of events leads to more iron retention and anaemia unless the root cause is diagnosed and treated. The study determined the prevalence of anaemia, iron deficiency and anaemia of inflammation in children in malaria endemic Limbe - Cameroon and how different social and clinical factors as well as inflammatory cytokines influence the concentration of haemoglobin and ferritin.
The overall anaemia prevalence of 67.5% is higher than the national prevalence of 62.5% recorded in children under five years [46], lower than the 77.7% obtained by Asoba et al. [29] in the under-fives in some parts of the Mount Cameroon area, and comparable to 66.7% obtained in children in the Western Region of Cameroon [47]. This again confirms anaemia as a severe public health problem in the Mount Cameroon area hence, there is a dire need to re-strategize the current control methods being employed.
The overall iron deficiency prevalence (34.6%) is comparable to those obtained in Kenyan (36.9%) and Ugandan (36.5%) children [48], higher than 18.2% reported by Nazari [49] in Iranian children, and lower than 76.1% and 51.1% reported in children in India [50] and in a rural area in Cameroon [47], respectively. This high prevalence observed in Cameroonian children may be a result of poor feeding practices despite having a vast diversity of food as recently reported in a study in the same area [51]. In that study inadequate weekly consumption of meat and plantain (which are iron-rich) and fruits, (which facilitate iron absorption) were reported risk factors for anaemia, and iron-deficiency has been established as the main cause of anaemia [1]. Meanwhile iron deficiency anaemia prevalence (12.9%) was lower than the recorded 33.5% in children in the Gaza Strip [52]. This difference may be attributed to the different age strata used in the study. Whilst our study population included adolescents in both urban and semi-urban setting, those in Gaza were under-fives and lived in a setting already compromised by being marginalized.
Observation from the study revealed anaemia of inflammation prevalence (30.2%) is comparable to the ID prevalence (34.6%). This is in line with studies that say ID and AI often co-exist and together cause most of the anaemia encountered in disease-prone areas [1]. A plausible explanation is that during AI, iron absorption from the intestines is restricted leading to iron retention in the recticulo-endothelial system as ferritin thus causing ID [16]. Hence, the intensity of inflammation may be directly proportional to the amount of iron sequestered as observations from the study demonstrated a positive correlation between ferritin and the pro-inflammatory markers.
Sex-wise, findings from the study showed males had a higher prevalence of anaemia than females. Correspondingly, ID and IDA prevalence were higher in males than females. The high proportion of IDA in males than females is in line with Nazari et al. [49] and Ewusie et al. [53] in Ghana. This may be explained by the fact that the iron requirement for growth is higher in males than in females [54] and they gain more weight during their first years of life [55]. This may imply that ID is among the major contributors of the anaemia observed in this group. Conversely, AI was more prevalent in females, which is to be expected as they had a higher proportion of inflammation and therefore probably accounted for the observed anaemia than did ID. However, as a limitation, it is uncertain if the inflammatory process was acute or chronic since alpha 1-acid glycoprotein (AGP) which is more reliable in distinguishing past from present infection than CRP [56] was not assayed.
Findings from the study demonstrated children 12–15 years old had a higher occurrence of anaemia, ID and IDA. This is probably because there is a peak in iron requirements at adolescence resulting from expansion of red blood cell mass and growing muscle tissues [57]. Also, there is a possibility that adolescents tend to frequently snack and take carbonated drinks rather than eat proper meals or consume vegetables and fruits; these snacks are usually overly processed and may not contain the much-needed iron to meet their bodies’ demand.
In many African countries iron deficiency usually goes unnoticed except when diagnosed in the hospital in the cause of finding causes for another ailment [8]. This may account for the high prevalence within the community when compared with those enrolled at presentation in the hospital. Further observation demonstrated ID was more prevalent in children whose parents work in the civil service whereas anaemia and IDA was more common in children whose parents’ main occupation is fishing. Whilst being a civil servant may ensure a steady source of income, it is no guarantee that the quality of food consume by the children in these household is iron-rich or promote iron-absorption. Furthermore, in this conflict-hit area, food security is a challenge in many of such households offering hospitality to family members and other internally displaced individuals who have fled the violence in search for food, peace and security. This may have led to low dietary diversity as quantity will be preferred over quality. Moreover, the anaemia and IDA observed in children whose parent/caregiver were fishermen may be attributed to the deficiency in iron observed or more likely the result of blood loss due to some other infection than malaria as the negative trend observed between haemoglobin and malaria status in the regression model was not significant.
Relating to family size, children in homes with 6–10 members had a higher prevalence of ID than in homes with less than 5 members. This finding is in conformity with Psirropoulou et al. [58] in Greek children 1‒2 years old. A reasonable explanation may be that in large homes, iron intake may be reduced after reduction in food portions as food is spread more widely. Furthermore, these children may be more exposed to infections and other parasites. As a limitation in the study, the effects of other infections such as bacterial or helminths were not investigated, which would have divulged to what extent they contribute to the burden of ID.
ID and IDA observed in afebrile children may have resulted from inflammatory response to an infection which the immune system was trying to fight off as observations from this study revealed higher ID prevalence in malnourished and malaria negative children. In areas of high malaria transmission people develop some degree of immunity so, harbouring parasites without overt fever or malaria-linked symptoms is common [59]. Moreover, afebrile children may have been harbouring other blood-sucking parasites such as intestinal parasites which cause iron deficiency by direct blood loss resulting from intestinal bleeding, or appetite loss leading to reduced food intake or may prevent nutrient from being absorbed. [60]. However, we did not assess intestinal parasites thus their role in iron deficiency in this study cannot be ascertained.
Congruent with previous studies [48, 61, 62,] malaria negative children had a higher prevalence of ID. The sequestration of iron in macrophages and liver cells in times of deficiency starves the malaria parasite [63] of iron thus serving as a protection against the disease in African children. It may also be that the production of nitric oxide, which has been shown to be detrimental against the malaria parasite, increases in ID states [64]. Hence, a probable increase in nitric oxide may be the cause of the high IDA burden seen in non-malarious children.
Both ID and IDA were common in undernourished than well fed children in accordance with Hagan et al. [65] even though no significant difference was observed with ID. It is expected that undernourished children will be iron deficient and anaemic, as the association between iron status and malnutrition has been previously established [66]. The vicious cycle between malnutrition, iron deficiency and anaemia may lead to inflammation which will further exacerbate anaemia.
The significant negative correlation observed between IL-6 and haemoglobin concentration is in line with studies elsewhere [67]. IL-6 stimulates the production of hepcidin which is the main iron-regulatory hormone preventing absorption of iron from the intestines and release from macrophages leading to low iron levels which may result to anaemia. On another hand, being a pro-inflammatory cytokine, produced in an early response to TNF-α [68], IL-6 will lead to iron sequestration in the presence of inflammation or iron overload [67] by stimulating hepcidin to degrade ferroprotein, thereby reducing bone marrow supply of iron and thus decreasing serum iron concentration [69] leading to anaemia.
In line with Choucair et al. [70], haemoglobin concentration correlated negatively with IL-10 concentration. IL-10 is an anti-inflammatory cytokine and acts to reduce inflammation by reducing the production of pro-inflammatory cytokines and free radicals such as nitric oxide [71]. A reduction in pro-inflammatory cytokines will lead to a decrease in inflammation and may lead to an increase in haemoglobin. IFN-γ is another pro-inflammatory cytokine which together with TNF-α, is produced in response to malaria infection [72]. Its production suppresses ferritin [73] starving the parasites of iron but also fostering ID and IDA [74] hence the positive correlation observed between haemoglobin and IFN-y levels.
Ferritin has been reported to correlate with inflammatory markers being on one hand a promoter and on the other a regulator of inflammation. The positive link between IL-1β, IL-6, IFN-y, TNF-α, CRP and ferritin shows that inflammatory markers can induce the expression of ferritin [75]. TNF-α and IL-1β have been shown to work in synergy with IL-6 to increase the production of more TNF-α and IL-1β, thus more CRP which in turn causes a corresponding increase in ferritin concentration [75]. This cascade of events usually results in iron retention in the liver and macrophages hence anaemia. Also, the presence of ferritin may stimulate the production of more of these cytokines including the anti-inflammatory IL-10 and multifunctional IL-6 which act to reduce the inflammatory response. This is observed in the negative trend between ferritin and IL-10.
Although the study had as limitations not assessing other haemoglobinopathies, nutritional deficiencies and behaviours that may have the potentials of influencing markers of iron deficiency and anaemia, nevertheless, the variables evaluated are critical in portraying the burden of anaemia, ID and the contributions of inflammatory cytokines to markers of anaemia, a severe public health burden in the region. There is a dire need for regular monitoring of these burdens to provide accurate data for the development of sustainable control strategies to alleviate the poor health of these children.